Somatostatin is a tetradecapeptide having the structure: Ala--Gly--Cys--Lys--Asn--Phe--Phe--Trp--Lys--Thr--Phe--Thr--Ser--Cys--OH and has the properties of inhibiting the release of growth hormone, inhibiting the release of insulin and glucagon and reducing gastric secretion. This lack of specificity of the biological activity of somatostatin has led to an intensive search for analogs which exhibit a more specific biological activity. Somatostatin itself has a short duration of action because it is inactivated, inter alia, by aminopeptidases and carboxypeptidases present in vivo. This problem of the short duration of action has been partially solved in the prior art by preparing derivatives of somatostatin which have low solubility, thus attaining a slow release on subcutaneous injection. Once dissolved, however, the derivatives are no more stable to inactivation by aminopeptidases and carboxypeptidases than somatostatin itself.
Further efforts to provide peptides having a more specific biological activity and longer duration of activity than naturally occurring somatostatin and which are easier to prepare because of the smaller ring size have resulted in peptides having the structural formula: ##STR2## wherein
A is Phe, Tyr, O--Me--Tyr,
B is Phe, Tyr,
C is Thr, Val,
R is H or COOH,
wherein the ring formed by the peptide backbone contains 26 atoms and wherein the preferred peptide is illustrated by the following structural formula: ##STR3## wherein
R is H or COOH, and the pharmaceutically acceptable non-toxic acid addition salts and carboxylic acid salts thereof. Said prior art peptides are described in Veber, U.S. patent application Ser. No. 920,529, filed June 29, 1978.
Said prior art peptides differ from somatostatin by virtue of the fact that they lack an N-terminal amino group thus eliminating the group involved in enzymatic cleavage of the molecule by aminopeptidases. Furthermore, the deletion of the adjacent heteroatoms of the disulfide bridge of somatostatin increases the stability of the analogs in vivo by preventing enzymatic degradation by reductive cleavage. Therefore, said prior art peptides are more resistent to cleavage in vivo that somatostatin and thus have a prolonged duration of action.
The present invention provides peptides having somatostatin activity which are retro-enantiomeric peptides of those prior art peptides set forth in U.S. Ser. No. 920,529, filed June 29, 1978. The term retro-enantiomeric is intended to designate a peptide to which the sequence is reversed and the chirality at each residue is inverted relative to a parent peptide. Shemyakin, et al., Angew Chem., Int. Ed. Engl., 8, 492-499 (1969).